There are various phosphonale-phosphates known in the art. Among these are the gem-phosphonate-phosphates, structurally characterized by having one phosphonate group (--PO.sub.3 R.sub.2) and one phosphate group (--OPO.sub.3 R.sub.2) bound to the same carbon atom.
The synthesis of known phosphonate-phosphates has been characterized. D. Brittelli, J. Org. Chem., 1985, 50:1845-47, reports the formation of phosphinylethenyl phosphate from chloracetyl chloride and trialkyl phosphites in ether. S. J. Fitch and K. Moedritzer, J. Amer. Chem. Sec., 1962, 84:1876-79, report the formation of 1-hydroxy phosphonate-phosphates via a base mediated isomeric rearrangement of the corresponding 1-hydroxy bisphosphonates. See also A. Tromelin, et al., Phosphorous and Sulfur, 1986, 27:301-12. None of these references disclose a utility for the compounds synthesized.
U.S. Pat. No. 4,894,469 discloses a process for making halogenated phosphonate-phosphates by reacting, first, alkylene oxide and phosphorus (III) chloride, and second, reacting the resulting phosphate trialkylesters with a halogen-acyl halide. The product is said to be useful as a fire retardant. L. M. Nguyen, et al., J. Med. Chem., 1987, 30:1426-33, report the synthesis of gem-phosphonate phosphates having activities which alter lipid metabolism and plasma high density lipoprotein cholesterol levels in rats. See also UK Patent 2,079,285. These compounds are synthesized via the reaction of dialkyl acyl phosphonates with alkyl phosphite in the presence of 80-100 reel % dialkylamine.
Other bis-phosphorus compounds, particularly the bisphosphonates, reportedly have anti-inflammatory activity, see e.g., U.S. Pat. No. 4,746,654, Australian Patent 8551-534-A (Derwent 86-212293/33), or utilities in the treatment of abnormal calcium metabolism/deposition, see e.g., U.S. Pat. No. 3,683,080, and DE 3,719,513 (Derwent 89-000580/01). However, no anti-inflammatory properties have been reported for the gem-phosphonate-phosphates.
The general mode of synthesis of the phosphonate-phosphates has been well documented. The typical procedure utilizes a reaction where the corresponding bisphosphonate undergoes rearrangement in lhe presence of excess base to titan the phosphonate-phosphate. See e.g. Nguyen, et al, J. Med. Chem., 1987, 30:1426-1433. U.S. Pat. No. 3,808,237, however, describes a scheme in which a substituted ethane polyphosphonate is reacted with an epoxidizing agent to produce the corresponding epoxy ethane diphosphonate. The epoxy ring thus formed is opened ("de-oxiranized") to form the ethane diphosphonate. The same or similar procedure is employed in the production of the various diphosphonates described in U.S. Pat. Nos. 3,940,436, 3,944,599, 3,957,858, and 3,962,318.
The compounds of the invention differ from the prior art compounds in having an amino group at position 2 of the methylene moiety. The compounds of the invention are prepared by a novel process which comprises reacting an epoxy ethane diphosphonate with an amino compound. The synthesis of the epoxy ethane diphosphonate is known and is described in U.S. Pat. No. 3,808,237.
The opening of epoxides by amines to form amino-alcohols is precedented in the literature, see for example, R. C. Larock, Comprehensive Organic Transformations, 1989, VCH Publishers, pp. 508-511. However, the opening of the epoxide tetramethyl oxiranylidenebisphosphonate by amines, followed by rearrangement to produce the compounds of the invention, has not been reported.
Known gem-phosphonate-phosphates reportedly display lipid-lowering and antiatherosclerotic activity. However, no anti-inflammatory properties have been reported for gem-phosphonate-phosphates.
This invention discloses novel gem-phosphonate phosphates useful as antiinflammatories and in the treatment of arthritis. This invention also provides a process for the synthesis of the compounds of the invention.
U.S. Pat. No. 4,746,654 discloses bisphosphonates useful as anti-inflammatory agents. The compounds disclosed, however, are not related to the compounds of lhe invention.
Australian Patent 8551-534-A (Derwent 86-212293/33) discloses bisphosphonic acids and derivatives useful in treating abnonnal calcium and phosphorous metabolism and are useful in treating arthritis. The compounds disclosed, however, are not structurally related to the compounds of the invention.
UK Patent 2 079 285 discloses bisphosphonic acids and phosphonic-phosphates, and derivatives thereof, useful as hypolipemic agents. The structures disclosed neither encompass the compounds of the invention nor does the patent disclose an anti-inflammatory utility.
A published European patent application, EP 320 455, discloses bisphosphonic acids derivatives useful as regulators of calcium metabolism and as anti-inflammatories. The compounds disclosed, however, are not related to the compounds of the invention.
A published European patent application, EP 252 504, discloses bisphosphonic acids and derivatives thereof useful as regulators of calcium metabolism. The compounds disclosed, however, are not related to the compounds of the invention.
L. M. Nguyen, et al, J. Med. Chem., 1987, 30: 1426-33, report gem-phosphonate-phosphates which have anti-atherosclerotic potential. The compounds lack the amino group of the present invention.
U.S. Pat. No. 4,894,469 discloses a process for making halogenated phosphonophosphoric acid and esters thereof useful as fire retardants. The compounds disclosed lack the amino group of the present invention.
U.S. Pat. No. 3,808,237 discloses the synthesis of substituted epoxy ethane polyphosphates (bisphosphonates), which are useful as a starting material for the compounds of the invention. The compounds are disclosed as having utility as fire retardants.
S. J. Fitch and K. Moedritzer, J. Amer. Chem. Soc., 1962, 84:1876-79, report the formation of 1-hydroxy phosphonate-phosphates. However, the compounds lack the amino group of the present invention.
D. Brittelli, J. Org. Chem., 1985, 50:1845-47, describes lhe synthesis of phosphonate-phosphates from chloroacetyl chloride. However, the compounds lack the amino group of the present invention.
A. Tromelin, et al, Phosphorous and Sulfur, 1986, 27:301-12, report isomerization and hydrolysis studies on hydroxy methylene diphosphonates. The resulting compounds, however, lack the amino group of the present invention.
M. Kanaan and R. Burgada, Phosphorous and Sulfur, 1988, 37:217-29, disclose the synthesis of phosphonate-phosphates via the rearrangement reaction of bisphosphonaies.